Dissolution

 The dissolution testing serves as an important tool for
characterizing the biopharmaceutical quality of a product
at different stages in the life cycle . In early drug
development , in vitro dissolution properties are
supportive for choosing between different
alternative formulation candidates for further development
and for evaluation of active ingredients / drug substances .
 Tablets or capsules taken orally remain one of the most
effective means of treatment available. The effectiveness of
such dosage forms relies on the drug dissolving in the fluids
of the gastrointestinal tract prior to absorption into the
systemic circulation.
 “Dissolution is a standardized method for measuring the
rate of drug release from a dosage form and their
solubilization”
2

 The principle function of the dissolution test may be
summarized as follows:
•Optimization of therapeutic effectiveness during
product development and stability assessment.
•Routine assessment of production quality to ensure
uniformity between production lots.
•Assessment of ‘bioequivalence’, that is to say,production
of the same biological availability from discrete batches of
products from one or different manufacturers.
••Provide process control and quality assuranceProvide process control and quality assurance
•Prediction of ‘in-vivo’ availability, i.e. bioavailability
•To create a dissolution profile
•To asses the batch to batch quality
•It provide pharmaceutical scientist relationship between an in vitro
characteristic of a dosage form, and its in vivo performance.
3

•Nature of drug.
• pH.
• Solubility.
• Dissociation constant.
• Particle size.
• Proper selection of dissolution agent.
• Setting of in process parameters.
• Hardness.
• Thickness.
• Physical parameters of tester.
• Temperature
• Media deaeration
• Medium volume
etc.
4

TESTTEST IPIP BPBP USPUSP
TemperatureTemperature 36.5 to 37.536.5 to 37.5 °C°C 36.5 to 37.536.5 to 37.5 °C°C 3737± 0.5 °C± 0.5 °C
pH of MediumpH of Medium ± 0.05± 0.05 ± 0.05± 0.05 ± 0.05± 0.05
Time forTime for
withdrawalwithdrawal
± 2 %± 2 % -- ± 2 %± 2 %
Distance betweenDistance between
bottom of paddlebottom of paddle
and jarand jar
23 – 27 mm23 – 27 mm 23 – 27 mm23 – 27 mm 2525 ± 2 mm± 2 mm
RPMRPM ± 4 %± 4 % ± 4 %± 4 % ± 4 %± 4 %
5

Disintegration is defined as
that state in which any
residue of the unit , except
fragments of insoluble
coating or capsule shell ,
remaining on the screen of the
test apparatus is a soft mass
having no palpably firm core
Simply it is break down of
dosage in define condition
Dissolution
Dissolution is a standardized
method for measuring the
rate of drug release from a
dosage form .
Dissolution is breakdown as
well as release, solubilization of
drug
Generally performed for API
having less solubility.
Disintegration
6

The impartment apparatus as per USP are:
 Type I ( Basket Apparatus ) : The assembly consist of a vessel with
a hemispherical bottom, which may be covered , made of glass or other
inert , transparent material , a motor , a metallic drive shaft and a
cylindrical basket .
 Type II ( Paddle Apparatus ) : Use the same assembly from apparatus
1 , expect that a paddle formed from a blade and a shaft is used as the
stirring device .
 Apparatus 3 ( Reciprocating Cylinder ) : The assembly consist of a
set of glass reciprocating cylinders , inert fittings , a screen and a motor
and drive assembly to reciprocate cylinders vertically inside the vessels .
 Apparatus 4 ( Flow through Cell ) : The assembly consist of a
reservoir and a pump for the dissolution medium ; a flow through cell
and a water bath
7

 Temperature
 Shaft RPM
 Medium
 Bath Level
 Vessels
 Time
8

 Temperature control in tablet dissolution testing is critical as a
change in temperature has a linear effect on the dissolution rate.
Temperature should be measured with a calibrated
thermometer, either analogue or digital, and should normally be 37°C
 The specified temperature should be measure in each vessel prior
to each run commencing . There is a temptation to only
measure temperature in a few of the vessels and assume that
they are all the same. This may not necessarily be the case as
temperature gradients can occur within a water bath that effect the
speed of equilibration of all the vessels.
 Most dissolution baths display the temperature of the bath itself but
this should not be taken as an indication of the temperature
inside the vessel. Typically it is necessary to run the water bath
0.5°C or so above the required temperature to ensure the correct
temperature inside the vessel . If plastic vessels are used instead
of glass then this may be a greater difference.
9

 The USP limit for stirring is ± 4% of the set speed of the test . This level
of shaft control was set during the early days of equipment
manufacturing where surging motors (this temporarily increased
or decreased the speed) were difficult to control . All modern
equipment can now control the speed to within ± 0.5 rpm so this
problem is rare . However the RPM still needs to be
measured periodically with a suitable tachometer.
 For Immediate release tablets, baskets at 100 RPM and Paddles at 50 or 75
RPM are commonly used.
 The RPM outside 25 and 150 are not appropriate because of inconsistency
of hydrodynamics below 25 rpm and turbulence above 150 rpm
10

 Selection of dissolution medium is based on the discriminatory
capabilities,ruggedness and stability of the analyte in the test medium.
 Key factors are solubility of the drug and solution stability.
 Properties that can affect the dissolution are release
mechanism,disintegration rate presence of solubility enhancers and
other excipients.
 Another requirement for developing a dissolution procedure is to have
sink conditions.
 In some cases surfactants are used like SLS or Polysorbate 80. These
help to enhance the drug solubility.
 Also the medium selection depends upon the location of availability of
the drug, for eg
 For release in stomach it is water or 0.1n HCl
 For release in Intestine it is Buffer pH 6.8
 For release in Pancreas it is buffer containing enzymes
11

 Media degassing is important as dissolved gases can causes
bubbles to form , which may change the result of the test .
 High results can occur when the bubbles adhere to the surface of
the tablet particles, increase their buoyancy, and raise them to a
higher part of the vessel where the media flow is quicker.
 Lower results can occur if the bubbles adhere to the surface of the
basket or the tablet forming a physical barrier between the tablet
and the media.
12

 Helium sparging
 Heating and filtering
 Vacuum degassing
Method
% Reduction
(approximate)
USP 84.9 ± 11%
Filtering only at room
temperature
65 ± 3%
Heating to 45°C 10 ± 14%
Boiling 49 ± 3%
Vacuum degassing 50-90%
13

 A releasing medium is the one that promotes solubilization of the drug
substance from a pharmaceutical dosage form without further
qualification .
 A discriminating medium is the one where the more subtle aspects
of the pharmaceutical dosage form can be differentiated by
observing their individual rates of dissolution . Particle size , crystal form,
salt form , presence of water of hydration, differences in the
manufacturing processes ,and so forth , may all affect the dissolution
performance . The dissolution test should be sensitive to any attribute
that may affect the in vivo performance of the product.
14

 The level of a dissolution bath is often overlooked. It should not be
assumed that the laboratory bench is level . This is one of the
parameters that should be checked on installation and some
dissolution testers have an in-built level checking device.
 Testers which are not level can give erroneous results and the media
rotation is not linear within the vessel.
 Level should be tested front to back as well as side to side . A
calibrated level will provide an accurate measurement of this. If the
bath is moved for any reason then this parameter will need to be re-checked.
15

 Vessel design is something that is often overlooked by the analyst. The
USP allows for a significant variation in the specification of the vessels
with a height of 160-170mm and an ID of 98-106mm. This variation
means that if vessels are changed in the bath then the paddle height
and centering measurements need to be rechecked. If the vessels
are serialized then they should be kept in the same position. As well as
the physical dimensions the vessels should be smooth and
scrupulously clean . Small ridges on the inside of the vessel can
greatly increase the dissolution rate whilst scratches and sticky or
gummy patches can reduce them.
16

 Introduction to Sampling : Almost every dissolution test relies on
samples being taken to produce a result and anything which affects the
accuracy of a sample should therefore be avoided. Sampling errors
are very common and are often the cause of erroneous results. The
sampling position is critical but so to is the type of sampling probe used.
 The sampling position is important particularly for tests with baskets
as there is often a concentration profile between the bottom of the
vessels and the stirring element . It is less noticeable with paddles as
the extra agitation provides for a more uniform flow profile. The USP
defines the sampling point as "A zone half way between the top of the media
and top of the paddle or basket not less than 1cm from the vessel
wall". Therefore the sampling position will be different for 500ml and
900ml tests. This can create problems for equipment that uses ‘through
the shaft’ sampling.
18

 "A zone half way between
the top of the media and top
of the paddle or basket not
less than 1 cm from the
vessel wall".
19

 Where a single time specification is given , the test may be concluded in
a shorter period . If two or more times are specified , specimens are
to be withdrawn only at the stated times, within a tolerance of ± 2 % .
 The duration of test is decided by finding the optimum time required for
reaching the peak plasma concentration
“ Q “ Value :
The quantity , Q , is the amount of dissolved active ingredient
specified in the individual monograph , expressed as a percentage of the
labeled content
22

 After the dissolution is over , combine the equal volumes of
filtered solutions of the six or twelve individual specimens
withdrawn and use this solution as a pooled solution .
StagesStages
NumberNumber
TestedTested
Acceptance CriteriaAcceptance Criteria
S 1S 1 66 Average amount dissolved is not lessAverage amount dissolved is not less
than Q + 10 % .than Q + 10 % .
S 2S 2 66 Average amount dissolved ( S 1 + S 2 ) isAverage amount dissolved ( S 1 + S 2 ) is
equal to or greater than Q + 5 % .equal to or greater than Q + 5 % .
S 3S 3 1212 Average amount dissolved ( S 1 + S 2 + S 3)Average amount dissolved ( S 1 + S 2 + S 3)
is equal to or greater than Q .is equal to or greater than Q .
23

Stage Number TestedNumber Tested Acceptance CriteriaAcceptance Criteria
S 1S 1 66 Each unit not less than Q + 5 % .
S 2S 2 66
Average of 12 units (S 1 + S 2 ) is equal
to or greater than Q , and no unit is less
than Q – 15 % .
S 3S 3 1212
Average of 24 units (S 1 + S 2 + S 3 )
is equal to or greater than Q , not more
than 2 units are less than Q – 15 %,
and no unit is less than Q – 25 % .
24

A 1A 1 66 No individual value exceed 10%
dissolved.
A 2A 2 66
Average of 12 units (A 1 + A 2 ) is Not
more than 10% dissolved,and no
individual unit is greater than 25%
dissolved.
A 3A 3 1212
Average of 24 units (A 1 + A 2 +A3 ) is
Not more than 10% dissolved, and no
individual unit is greater than 25%
dissolved.
25

B 1B 1 66 Each unit not less than Q + 5 % .
B 2B 2 66
Average of 12 units (B 1 + B 2 ) is equal
to or greater than Q , and no unit is less
than Q – 15 %
B 3B 3 1212
Average of 24 units (B 1 + B 2 + B 3 )
is equal to or greater than Q , not more
than 2 units are less than Q – 15 %,
and no unit is less than Q – 25 % .
.
26

L 1L 1 66 No individual value lies out side each of the stated range
and no individual value is less than the final test time
L 2L 2 66
Average of 12 value (L 1 + L 2 ) is lies within each of the
stated range and is not less than the stated amount at the
final test time; none is more than 10% of labeled content
outside each of the stated range;and non is more than
10% of labeled content below the stated amount at the
final test time
L 3L 3 1212
Average of 24 value (L 1 + L 2 +L3 ) is lies within each of
the stated range and is not less than the stated amount at
the final test time; Not more than 2 of 24 unit are more
than 10% of labeled content outside each of the stated
range;Not more than 2 of 24 are more than 10% of
labeled content below the stated amount at the final test
time. Non of the units is more than 20% of labeled
content outside each of the stated range or more than
20% of labeled content below the stated amount at the
finaltest time.
27

 Assuming that the determinative step involves spectrophotometry with
the analysis conducted at a given wavelength, several factors may
produce apparently higher dissolution percentages than what was
found in the Assay. Degradation of the compound under the test
conditions is a possibility as is additive interference due to excipients.
These types of interferences should be identified in method
development and validation . Of course, errors in the preparation of the
standard solution(s) could also play a role . Again, careful attention
to detail , such as the requirement to prepare check standards and
familiarity with the absorptivity of the standard solution, can provide
protection against these types of problems. It is important to consider
the possibility that the higher values found in the dissolution sample
may be true. The assay value is typically the result of the analysis of a
composite of multiple dosage units and, as such, represents an average. If
individual dissolution values that are higher than the assay are observed ,
content uniformity might be to blame. The amount available for
dissolution in the higher-than-assay dosage unit may indeed be higher
than the amount in the assay composite. If consistently higher values are
found in dissolution than in the assay, it may indicate that the validating
information for the dissolution test should be reevaluated.
28

 Physical : This calibration is carried out on monthly basis to check
the critical physical parameters of the instrument.(Frequency as per sop)
 Chemical : This is calibration is carried out during installation of the
instrument and after every six month to check the apparatus suitability
(Frequency as per sop)
29

Sr.n.Sr.n. ParameterParameter Acceptance Criteria ( USP )Acceptance Criteria ( USP )
0101 Head Co-PlanarityHead Co-Planarity Perfectly HorizontalPerfectly Horizontal
0202 Rotational SpeedRotational Speed ±± 2 % of the stated value2 % of the stated value
0303 Temperature checkTemperature check 3737 ± 0.5 ° C± 0.5 ° C
0404 Calibration of timerCalibration of timer ±± 2 % of the stated value2 % of the stated value
0505 Wobble checkWobble check NMT 0.5 mm for paddleNMT 0.5 mm for paddle
NMT 1.0 mm for basketNMT 1.0 mm for basket
0606 Distance from paddle / basketDistance from paddle / basket
bottom to the bottom of the jarbottom to the bottom of the jar
2525 ±± 2 mm2 mm
0707 Integrity check and mesh size ofIntegrity check and mesh size of
basketbasket
The mesh should be intact . The no. ofThe mesh should be intact . The no. of
opening should be 40 per linearopening should be 40 per linear
inchinch
0808 Distance between the shaft axis andDistance between the shaft axis and
the vertical axis of the vesselsthe vertical axis of the vessels
The centering should beThe centering should be
<< 2mm2mm
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 Use Prednisone 10mg Tablets (Current lot)and follow instruction given in related
certificates for standard and test preparation and calculate % of drug release and perform
PVT test
Calculation of %CV:
 Run 1 : x1,x2, …….., xnin natural log scale, :Ln x1, Ln x2, …….., Ln xn
 Run 2 : xn+1,xn+2, …….., xnin natural log scale, :Ln xn+1, Ln xn+2, …….., Ln x2n
 1st
stage of two-stage for n=6, 7, 8 and Single-stage for n=12, 14:
 GM1 = exp (average (Ln x1: Ln xn))

% CV = 100*sqrt(exp (var (Ln x1: Ln xn))-1)
 Single-stage or 2nd
stage of two-stage for n=6, 7, 8:
 GM = exp (average((average (Ln x1: Ln xn)), (average (Ln xn+1: Ln x2n)))) = exp (average (Ln x1:
Ln x2n))
 % CV = 100*sqrt(exp (average((var(Ln x1: Ln xn)), (var(Ln xn+1: Ln x2n))))-1)
 exp: exponential (ex
), var: variance, sqrt: square root, * : multiply, 100: conversion factor
to percentage
31

 Complete Validation Toolkit
 Depth Setting Gauge
 Tachometer ( Optical )
 Thermometer
32

 Universal Instrument Level
 Vessel Centering Gauge
 Vibration Meter
 Wobble meter
33

◦ Keep the surroundings clean and tidy of dissolution apparatus.
◦ Any spillage of liquid is to be immediately mopped.
◦ Finally before leaving the place, ensure that the dissolution vessels are
washed, the heater is turned off and the spindles have been removed &
washed
◦ Do not start the heater if there is no water in the dissolution bath up to
the indicated level.
◦ The Bath should be always filled with distilled water only. In order to
avoid germs propagation the liquid can be sterilized with a suitable
preservative (e.g. 0.1% w/v Benzalkonium chloride).
◦ To clean the jars and heater bath do not use any aggressive material or
strong solvents which can spoil the jars
34

◦ Do not hold the stirrer while in operation.
◦ Do not pull or force the paddle or the basket
◦ Do not over tighten the stirring element
◦ It is not possible to lift the stirrer unit, while paddles are rotating so first
stop the stirring process then lift the stirring assembly
◦ Do not disturb the sensor tube while cleaning the tank.
35

Dissolution

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Dissolution